This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. FCHL affects 1-2% of the population of Westernized societies and is one of the most common genetic lipid disorders in patients with coronary artery disease. Because of their high incidence of CAD West Virginians may be at greater risk for this disorder compared to the general US population. The overall objective of this project is to identify gene(s) that predispose to FCHL using family-based linkage analysis and association methods. The central hypotheses are that there are specific genes that conger susceptibility to FCHL and that there is genetic heterogeneity (i.e. more than one gene or set of genes can give rise to the disease). Our first specific aim is to identify FCHL susceptibility loci by linkage analysis on a genome-wide set of markers and on a small set of previously identified FCHL candidate loci. Our second specific Aim #2 is to perform genetic fine mapping on the susceptibility loci in order to narrow the region of interest. A new specific aim was approved at the beginning of year 4. The role of methionine synthase and betaine homocysteine methyltransferease in homocysteine metabolism and apoptotic response to homocysteine will be tested in human umbilical vein endothelial cells (HUVECs).